KR101179638B1 - Adsorbent for the removal of blood cells - Google Patents

Abstract

An adsorbent for the removal of blood cells, which is formed from a hydrophobic polymer resin and has a surface center line average roughness (Ra) of 5 to 100 nm. The hydrophobic polymer resin is preferably a polyarylate resin (PAR), polyethersulfone resin (PES), polysulfone resin (PSF), or a polymer alloy consisting of two or more of these resins. The adsorbent for the removal of blood cells can take the form of beads, hollow fibers, or solid fibers.

Description

ADSORBENT FOR THE REMOVAL OF BLOOD CELLS

The present invention relates to a blood cell removal adsorbent for removing white blood cells and platelets contained in blood.

In recent years, leukocyte adsorbers have become popular as treatment devices for inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). In the leukocyte adsorber, a therapeutic effect is exerted by directly removing leukocytes, which cause inflammation, from the blood using the principle of adsorption and filtration. In treatment with a leukocyte adsorber, unlike treatment with a drug, the smallest side effect is the biggest feature. In the leukocyte adsorber which has been put to practical use, a method using a carrier having a certain surface roughness or a method using a filter of ultrafine polymer fibers has been proposed.

For example, Patent Literature 1 discloses a carrier for granulocyte adsorption having a concave-convex surface having a centerline average roughness (Ra) of 0.2 μm to 100 μm and a concave-convex mean spacing (Sm) value in a range of 5 μm to 200 μm. Is disclosed.

Moreover, in patent document 2, the at least 2 sort (s) of polymer whose number average molecular weight is 10000 or more and differs in the coagulation value is melt | dissolved in the solvent which is compatible with each polymer, The said polymer solution A method for producing porous beads is proposed, which is prepared by coagulating in a coagulating solution containing a nonsolvent in the form of droplets.

In addition, Patent Document 3 discloses the destruction of blood cells, which is difficult to prevent with a filter such as a nonwoven fabric by arranging fibers made of organic polymers at high regularity, that is, arranged substantially parallel to each other, and circulating blood therebetween. And techniques for capturing white blood cells on the surface of fibers while overcoming problems such as coagulation of blood are disclosed.

These methods are mainly designed to remove white blood cells, such as granulocytes and lymphocytes, from the blood of cancer patients or patients with abnormalities in the immune system. By the way, recent studies have revealed that not only leukocytes but also platelets in blood are involved as inflammatory cells, especially in inflammatory diseases such as autoimmune diseases.

[Patent Document 1]

Japanese Patent Application Laid-Open No. 5-168706

[Patent Document 2]

Japanese Patent Application Laid-Open No. 62-243561

[Patent Document 3]

European Patent No. 1931404

The present invention is to provide an adsorbent for blood cell removal that is less likely to cause in-circulation coagulation or the like during blood flow and can efficiently remove leukocytes and platelets.

In one embodiment of the present invention, there is provided an adsorbent for removing blood cells. The blood cell removal adsorbent is formed of a hydrophobic polymer resin, and the surface centerline average roughness Ra is 5 to 100 nm.

By using this type of blood cell removal adsorbent, white blood cells and platelets can be efficiently removed while suppressing the occurrence of blood coagulation in a column or a circuit during blood flow.

In the above aspect, the hydrophobic polymer resin may be a polyarylate resin having a repeating unit represented by the following general formula (1).

In general formula (1), R1 and R2 are C1-C5 lower alkyl groups, and R1 and R2 may be same or different, respectively.

In the above aspect, the hydrophobic polymer resin may include a polyether sulfone resin having a repeating unit represented by the following formula (2) or formula (3).

In general formula (2), R <3> and R <4> is a C1-C5 lower alkyl group, and R <3> and R <4> may be same or different, respectively.

In the above aspect, the hydrophobic polymer resin may include a polyarylate resin having a repeating unit represented by the general formula (1) and a polyether sulfone resin having a repeating unit represented by the general formula (2) or the general formula (3). .

The adsorbent for blood cell removal of the above aspect may be in a bead shape. In addition, the adsorbent for removing blood cells of the above aspect may be a hollow fiber or a solid yarn fiber. In addition, the above-described adsorbent for removing blood cells can be used for removing white blood cells and platelets in blood.

In addition, the appropriate combination of the above-described elements can also be included in the scope of the invention seeking protection by a patent by the present patent application.

According to the present invention, problems such as coagulation in the circuit are less at the time of blood flow, and white blood cells and platelets contained in the blood can be efficiently removed.

1 is a schematic view of a porous beads manufacturing apparatus used for the manufacture of beads for blood cell removal;
2 is an exploded perspective view showing an outline of a blood cell removal module using blood cell removal beads according to Example 1;
3 is an AFM image (10 μm × 10 μm) of the blood cell removal beads of Example 3,
4 is an AFM image (10 μm × 10 μm) of the blood cell removal beads of Comparative Example 3,
5 is an exploded perspective view showing an outline of a blood cell removal module using hollow fiber according to Example 4;
6A is a perspective view of the structure of a blood cell removing module according to the embodiment;
6B is an exploded perspective view of the structure of the blood cell removal module according to the embodiment;
7 is a perspective view of an example of a structure of a blood cell removal module in an embodiment of the present invention;
8 is an exploded perspective view of an example of a module for removing blood cells in an embodiment of the present invention;
9 is a view for explaining an example of a method for manufacturing a blood cell removal module in an embodiment of the present invention;
FIG. 10 is a view for explaining the configuration of the cylindrical blood cell removal adsorbent in the embodiment of the present invention, showing an example of a cross section taken along the line AA of FIG. 8;
It is a figure explaining the structure of the cylindrical blood cell removal adsorption body in embodiment of this invention, It is a figure which shows another example of the cross section along the AA line of FIG.

[First Embodiment]

The blood cell removal adsorbent according to the embodiment is formed of a hydrophobic polymer resin, and the centerline average roughness Ra of the surface is 5 to 100 nm.

By making the surface material into a hydrophobic polymer resin, the adsorptivity of leukocytes and platelets such as granulocytes and lymphocytes can be improved by hydrophobic interaction.

As the hydrophobic polymer resin, polyarylate resin (PAR), polyethersulfone resin (PES), polysulfone resin (PSF) or a polymer alloy of these resins is suitable.

Polyarylate resin is resin which has a repeating unit represented by following General formula (1). It is preferable that the number average molecular weight of polyarylate resin is 20,000-30,000. When the number average molecular weight of polyarylate resin is larger than 30,000, since surface unevenness | corrugation becomes large too much, it becomes difficult to form appropriate surface unevenness | corrugation. On the other hand, when the number average molecular weight of polyarylate resin is less than 20,000, the intensity | strength of the blood cell removal adsorbent will become low, and the manufacturing yield of a blood cell removal adsorbent will worsen.

In general formula (1), R1 and R2 are C1-C5 lower alkyl groups, and R1 and R2 may be same or different, respectively. As R1 and R2, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, etc. are mentioned, for example. Preferred R1 and R2 are methyl groups.

The polyarylate resin is not particularly limited as long as the repeating unit represented by the general formula (1) is the main repeating unit, and may contain other repeating units as long as the object of the present invention is not impaired.

Polyether sulfone resin is resin which has a repeating unit represented by following General formula (2) or General formula (3). It is preferable that the number average molecular weight of polyether sulfone resin is 15,000-30,000. If the number average molecular weight of the polyether sulfone resin is larger than 30,000, the surface irregularities become too large, so that it is difficult to form appropriate surface irregularities. On the other hand, when the number average molecular weight of polyether sulfone resin is smaller than 15,000, the intensity | strength of the blood cell removal adsorbent will become low, and the manufacturing yield of a blood cell removal adsorbent will worsen.

In general formula (2), R <3> and R <4> is a C1-C5 lower alkyl group, and R <3> and R <4> may be same or different, respectively. As R3 and R4, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, etc. are mentioned, for example. Preferred R1 and R2 are methyl groups.

By setting Ra on the surface of the blood cell removal adsorbent to 5 to 100 nm, the adsorbability of leukocytes and platelets can be further improved. In addition, it is difficult in manufacturing to make Ra of the surface of the adsorbent for blood cell removal smaller than five. On the other hand, when Ra on the surface of the blood cell removal adsorbent is larger than 100 nm, the contribution to the adsorption of platelets (size 2 to 4 µm) decreases, and production by the coagulation method becomes difficult. Ra on the surface of the adsorbent for removing blood cells can be measured by AFM (atomic force microscope). The measurement area by AFM is 10 μm × 10 μm.

The blood cell removal adsorbent according to the embodiment is suitably used for the leukocyte and platelet removal therapy. Specifically, leukocytes and platelets can be removed from the blood by filling the column with the blood cell removal adsorbent according to the embodiment and flowing the blood into the column. In this case, by filling the column with an adsorbent for removing blood cells, a flow path is formed between adjacent adsorbents for removing blood cells, thereby facilitating securing of blood flow, thereby suppressing the occurrence of blood coagulation. In addition, white blood cells and platelets can be easily and efficiently removed from blood without using complicated devices.

As for the form of the blood cell removal adsorbent, fibers such as beads, hollow fiber shapes or solid yarn shapes are suitable.

When the form of the blood cell removal adsorbent is in the form of beads (hereinafter referred to as beads for blood cell removal), the diameter of the beads is preferably 0.5 to 5 mm. The following effects can be acquired by making the adsorbent for blood cell removal into the bead shape.

(1) Compared with LCAP (lymphocyte ablation therapy) using an ultrafine fibrous nonwoven fabric, even when the viscosity of the patient's blood is high and the risk of coagulation in the column is high, the pressure loss in the column is relatively small and relatively low. Less problems such as coagulation can be used.

(2) Unlike LCAP, since lymphocytes are not removed, the risk of removing memory cells related to immunity is reduced.

(3) Compared with GCAP (granulocyte removal therapy) using the same beads-like adsorbent, more platelets can be removed, so that the symptoms of inflammation derived from platelets can be effectively suppressed.

(4) Since the treatment can be performed only by passing the whole blood through the disposable column, a simple and highly stable treatment can be provided.

(5) Since an expensive apparatus such as a centrifuge is not required, the treatment can be performed at low cost.

In addition, when the shape of the blood cell removal adsorbent is a hollow fiber shape and a solid yarn shape (hereinafter, referred to as a hollow fiber for blood cell removal and a solid yarn for blood cell removal, respectively), the outer diameter is preferably 0.1 to 5 mm. By setting the adsorbent for blood cell removal into a hollow fiber shape or a solid yarn shape, the following effects can be obtained in addition to the above-described effects.

(1) The adsorbent for removing blood cells has a hollow fiber shape or a solid yarn shape, so that the blood viscosity of the patient is higher than that of the LCAP using the microfiber nonwoven fabric, and the risk of coagulation in the column is relatively high. Can be used.

(2) By using the form of hollow fiber and solid yarn, the production efficiency of the blood cell removal adsorbent can be increased, and the manufacturing cost can be reduced.

[Production method of beads for removing blood cells]

The manufacturing method of the blood cell removal beads which concerns on embodiment is demonstrated. First, a hydrophobic polymer resin is dissolved in N-methyl-2-pyrrolidone (hereinafter referred to as NMP) to adjust a polymer solution (stock solution). A mixture of NMP and water is used as a coagulation solution. The said polymer solution is dripped at the height of about 10 cm from the liquid level of a coagulation tank with a nozzle of 0.25 mm internal diameter (refer FIG. 1). After solidifying sufficiently in the coagulation liquid, the beads for blood cell removal can be obtained by washing with distilled water.

1 is a schematic diagram of a blood cell removing bead manufacturing apparatus 100 used to manufacture blood cell removing beads. The stock solution stored in the stock solution tank 110 is supplied to the nozzle 130 by the pump 120. The raw liquid supplied to the nozzle 130 is dripped from the nozzle 130. Below the nozzle 130, the coagulation liquid bath 140 in which coagulation liquid is stored is provided. In addition, the coagulating liquid bath 140 may be provided with a rotating body (not shown) for causing a swirl flow in the coagulating liquid.

The overflow pipe 142 is provided in the upper part of the coagulating liquid tub 140. When the liquid level of the coagulant liquid stored in the coagulant bath 140 reaches the installation port of the overflow tube 142, the overflowed coagulant liquid flows through the overflow tube 142 to the coagulant liquid recovery tank 144. It is recovered. In addition, it is preferable to provide a mesh 143 having a smaller hole than the diameter of the blood cell removal beads 150 generated in the coagulating liquid bath 140 in the installation hole of the overflow tube 142. According to this, mixing of the blood cell removal beads 150 into the coagulation liquid recovery tank 144 as foreign matter is suppressed.

The coagulated liquid recovered in the coagulated liquid recovery tank 144 is pumped up using the coagulated liquid circulation pump 146 and stored in the coagulated liquid bath 140 again. The amount of the coagulant liquid supplied from the coagulant liquid recovery tank 144 to the coagulant liquid bath 140 is detected by the flow meter 147, and an appropriate amount is supplied to the coagulant liquid bath 140 using the coagulant liquid supply amount adjustment valve 148. do. Thus, since the effective use of the coagulation liquid can be circulated by circulating the overflowed coagulation liquid, the manufacturing cost of the blood cell removal beads 150 can be reduced.

The stock solution dropped from the nozzle 130 toward the coagulation bath 140 is solidified into a spherical shape in the coagulation solution, and a blood cell removing beads 150 are formed. By dropping the stock solution in the coagulation solution, the spherical blood cell removal beads 150 can be obtained more stably and with high yield.

The solidified blood cell removal beads 150 are discharged from the lower portion of the coagulation bath 140 and are held in a sieve 160 having a smaller hole than the diameter of the blood cell removal beads 150. The amount of the coagulant liquid including the blood cell removal beads 150 discharged from the coagulant bath 140 is appropriately controlled by the coagulant discharge valve 170. The coagulant liquid discharged from the coagulant bath 140 together with the blood cell removing beads 150 is recovered to the coagulant recovery tank 144 and reused.

[Method of Manufacturing Hollow Fiber for Blood Cell Removal]

The manufacturing method of the hollow yarn for blood cell removal which concerns on embodiment is demonstrated. First, a hydrophobic polymer resin is dissolved in an organic solvent to prepare a spinning stock solution. The organic solvent is not particularly limited as long as it is a good solvent with respect to the hydrophobic polymer resin, and examples thereof include tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, and NMP. Among these, NMP is preferable as an organic solvent.

By using a double nozzle, the spinning stock solution is extruded together with the internal coagulant (an organic solvent containing water) and dropped into the external coagulant (an organic solvent containing water) to produce a hollow fiber for blood cell removal. have. As for the temperature at the time of spinning a hollow fiber for blood cell removal, about 5-15 degreeC is preferable. By setting the spinning temperature in this range, the stability of the spinning stock solution is improved, and phase separation and the like become less likely to occur. It is preferable that the ratio of the density | concentration of an internal coagulation liquid (core liquid) and an external coagulation liquid is 0.6-1.6.

[Manufacturing method of solid yarn for blood cell removal]

The manufacturing method of the solid thread for blood cell removal which concerns on embodiment is demonstrated. First, a hydrophobic polymer resin is dissolved in an organic solvent to prepare a spinning stock solution. The organic solvent is not particularly limited as long as it is a good solvent to hydrophobic polymer resin, and examples thereof include tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, and NMP. Among these, NMP is preferable as an organic solvent.

By using a normal nozzle (orifice), the spinning raw liquid is dropped together with the coagulating liquid (an organic solvent including water) to produce a solid thread for removing blood cells. As for the temperature at the time of spinning the solid thread for blood cell removal, about 5-15 degreeC is preferable. By setting the spinning temperature in this range, the stability of the spinning stock solution is improved, and phase separation or the like becomes difficult to occur.

[Second Embodiment]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, embodiments of the present invention will be described with reference to the drawings. Fig. 6A is a perspective view of the structure of the blood cell removal module according to the embodiment. 6B is an exploded perspective view of the structure of the blood cell removal module according to the embodiment. The blood cell removal module 10 includes a case 20 and a blood cell removal adsorbent 50.

The case 20 has a case body 21, a pair of meshes 30a and 30b, and a pair of headers 40a and 40b. The case main body 21 is a cylindrical member made of polycarbonate. In addition, the material of the case main body 21 is not limited to polycarbonate, You may use a well-known resin material, a metal material, or a composite material.

The pair of meshes 30a and 30b made of polyester are provided in the openings at both ends of the case main body 21, respectively. The meshes 30a and 30b have a hole smaller than the outer diameter of the blood cell removal adsorbent 50 described later, and the blood cell removal adsorbent 50 is held in the case by the mesh. In addition, the material of the mesh 30 is not limited to polyester, You may use a well-known resin material, a metal material, or a composite material.

The header 40a is provided in one opening part of the case main body 21 with the mesh 30a mentioned above interposed. The inlet part 22 which serves as a blood introduction path is provided in the header 40a. Moreover, the header 40b is provided in the other opening part of the case main body 21 through the mesh 30b mentioned above. The header 40b is provided with an outlet portion 24 serving as a discharge passage of blood after blood cell removal. The openings at both ends of the case main body 21 are sealed by the header 40a and the header 40b. In order to further ensure the sealing, a sealing member such as an O-ring may be provided between the header 40a and the case main body 21 and between the header 40b and the case main body 21.

The blood cell removal adsorbent 50 is housed inside the case body 21 sandwiched between the pair of meshes 30a and 30b. The blood cell removal adsorbent 50 is arranged inside the case main body 21 at random, in other words, in an irregular and non-fixed state. The blood cell removal adsorbent 50 is a hollow fiber or a solid fiber-like short fiber, the length of which is preferably 1 to 60% of the inner diameter of the case body 21, more preferably 18 to 56%. Do. Setting the length of the blood cell removal adsorbent 50 to less than 1% of the inner diameter of the case main body 21 causes a decrease in productivity. On the other hand, if the length of the blood cell removal adsorbent 50 becomes longer than 60% of the inner diameter of the case main body 21, since the fibrous blood cell removal adsorbents 50 interfere with each other in the case main body 21, Since free movement of each of the blood cell absorbents 50 is limited, once air is introduced into the fiber, it becomes difficult to fall out of the case. That is, since the air escape worsens, the remaining air is likely to cause blood coagulation in the blood. In addition, since the contact area between the blood cell removing adsorbent and the blood decreases, there is a possibility that the adsorption performance is lowered.

It is preferable that the filling rate of the adsorbent 50 for blood cell removal with respect to the volume of the case main body 21 is 20 to 60%. By setting the filling rate of the blood cell removal adsorbent 50 to 20% or more, the amount of blood required for blood purification is reduced, so that the burden on the patient can be reduced. On the other hand, when the filling rate of the blood cell removal adsorbent 50 is greater than 60%, it becomes difficult to charge, resulting in a decrease in work efficiency.

In addition, the blood cell removal adsorbent 50 is made of a hydrophobic polymer resin. According to this, since the surface of the blood cell removal adsorbent 50 becomes hydrophobic, not only granulocytes which are inflammatory cells but also platelets can be efficiently removed by hydrophobic interaction. In addition, while suppressing side effects, inflammation symptoms derived from autoimmune diseases can be suppressed.

As the hydrophobic polymer resin, the same resin as in the above-described first embodiment can be used. Therefore, the description thereof is omitted here.

By setting Ra on the surface of the blood cell removal adsorbent to 5 to 100 nm, the adsorbability of leukocytes and platelets can be further improved. In addition, as described above, it is difficult in manufacturing to make Ra of the surface of the blood cell removal adsorbent smaller than 5. On the other hand, when Ra on the surface of the blood cell removal adsorbent is larger than 100 nm, the contribution to the adsorption of platelets (size 2 to 4 µm) decreases. Ra on the surface of the adsorbent for blood cell removal can be measured by AFM (atomic force microscope). The measurement area by AFM is 10 μm × 10 μm.

According to the blood cell removal module described above, there is little irritation to the coagulation system, and blood coagulation is less likely to occur during treatment when used as a blood purification column for treatment. In addition, it is possible to improve air bleeding during priming (blood filling).

Moreover, since the adsorbent for blood cell removal can be manufactured with high production efficiency only by cutting | disconnecting the fiber of a hollow fiber shape or a solid yarn shape which can be continuously shape | molded, the cost of a blood cell removal module can be reduced.

[Third embodiment]

The blood cell removal module and the manufacturing method of the blood cell removal module in embodiment of this invention are demonstrated below. In addition, the same code | symbol is attached | subjected to the same structure in 1st, 2nd embodiment, and the description is abbreviate | omitted.

As shown to FIG. 7 and FIG. 8, the blood cell removal module 300 in this embodiment contains the cylindrical blood cell removal adsorption body 350 in the case 20. As shown in FIG. The case 20 has the case main body 21, the header 40a, 40b provided with the blood inflow outlets 22, 24, respectively, and a pair of mesh 30a, 30b as needed.

On the other hand, the cylindrical blood cell removal adsorbent 350, as shown in Figs. 8, 9 and 10, the blood cell removal adsorbent 54 composed of a plurality of hollow fiber-like or solid yarn-like fibers arranged. Both ends of the blood-removing adsorbent-integrated mesh-like cloth 60 fixed to the mesh-like cloth 52 through which blood is passed are wound up along the arrangement direction of the blood-removing adsorbent 54. Here, when fixing both ends of the blood cell removal adsorbent 54 to the mesh-like cloth 52 which can pass blood, both may be fixed using an adhesive agent, and the blood cell removal adsorbent 54 may be fixed. Both ends may be fused and fixed to a mesh-like cloth 52 through which blood can pass. In addition, in the case where the blood cell removal adsorbent 54 is a hollow fiber-shaped fiber, by using fusion (especially heat fusion) at the time of fixation, the hollows at both ends of the blood cell removal adsorbent are reduced compared to the fixing by the adhesive. It is easily encapsulated. Therefore, when used as the blood cell removal module 300, in a simpler method, the inflow of blood components into the hollow fiber is suppressed, and residual blood is prevented.

In addition, the manufacturing method of the cylindrical blood cell removal adsorbent 350 and the blood cell removal module in this embodiment is demonstrated using FIG. In addition, here, as a method of fixing both ends of the blood cell removal adsorbent 54 to the mesh-like cloth 52 which can pass a blood, it demonstrates as an example of fusion. As shown in FIG. 9, the blood cell removal adsorption body 54 which consists of several hollow fiber-shaped or solid-fiber fiber was arrange | positioned on the blood-tight network cloth 52 which consists of meshes, etc., and then, the blood cell Both ends of the removal adsorbent 54 are fused and fixed to the mesh cloth 52 using the fusion device 70, and the ends of the blood cell removal adsorbent 54 are sealed (S100). An adsorbent unitary mesh cloth 60 is formed. Here, the fusion apparatus 70 may use either means of thermal fusion or ultrasonic fusion. As described later, the blood cell removal adsorbent 54 is made of resin, while the mesh-like cloth 52 is also made of resin. Therefore, by using the fusion device 70, both ends of the blood cell removal adsorbent 54 and the mesh cloth 52 can be fixed without using an adhesive, and the blood cell removal adsorbent 54 can be fixed. The tip can be sealed. In addition, the outer end part may remain or cut | disconnect in the fusion | splicing part 56 of the obtained blood cell removal | adhesion body integrated mesh cloth 60 obtained. Next, as shown by a hollow arrow, the obtained blood cell removal adsorbent-integrated mesh cloth 60 is wound along the arrangement direction of the blood cell removal adsorbent 54 (S110) to form a spacer. A cylindrical blood cell removal adsorbent 350 including a bundle of blood cell removal adsorbents 54 interposed between the shape cloths 52 is formed (S112). In addition, the blood cell removal module of this embodiment is manufactured by accommodating the obtained cylindrical blood cell removal adsorbent 350 in the case 20. Instead of the fusion fixing described above, an adhesive may be used for fixing, and if necessary, both ends of the blood cell removal adsorbent 54 may be sealed with an adhesive.

In the obtained cylindrical blood cell removal adsorbent 350, the mesh cloth 52 functions as a spacer of the blood cell removal adsorbent 54 made of a plurality of hollow fiber or solid yarn fibers. The distance between fibers of the blood cell removal adsorbent 54 housed in the case 20 becomes substantially uniform in the blood cell removal module, and an appropriate gap is formed. Therefore, clogging of blood flow in the blood cell removal module is suppressed, and the blood cell removal module according to the present embodiment improves the blood cell adsorption efficiency, and also forcibly prevents the end of the blood cell removal adsorbent made of fibers as in the prior art. Since the mesh does not need to be fixed, the number of parts can be reduced and the manufacturing process can be simplified.

In addition, when the blood cell removal adsorbent 54 is hollow fiber, the hollows at both ends of the fused blood cell removal adsorbent 54 are sealed, so that the hollows of the blood cell removal adsorbent 54 are removed at the time of blood cell removal. The inflow of blood into the company is suppressed from developing residual blood.

In the cylindrical blood cell removal adsorbent 350 according to the present embodiment, not only one layer but also a plurality of layers of blood cell removal adsorbents 54 are arranged on the mesh cloth 52 and both ends thereof are fused together. It is wound up and is formed. An example of the structure of the cylindrical blood cell removal | adsorbing body 350 in this embodiment is demonstrated using FIGS. 10 and 11 which are sectional drawing along the A-A line of FIG. For example, in FIG. 10, the cylinder formed by winding the adsorbent 54 for blood cell removal arranged in one layer on the mesh-like cloth 52 and being fused and fixed along the arrangement direction of the adsorbent 54 for blood cell removal is formed. An adsorbent 350 for removing blood cells is shown. In addition, in FIG. 11, the cylindrical blood cells formed by winding the adsorbent 54 for blood cell removal arranged in two layers on the mesh-like cloth 52 along the arrangement direction of the adsorbent 54 for blood cell removal are formed. The removal adsorbent 350a is shown. How many layers of the blood cell removal adsorbent 54 are fused and arranged on the mesh cloth 52 is appropriately selected depending on the diameter and length of the blood cell removal adsorbent 54 and the viscosity of the blood to be passed.

Next, the blood cell removal adsorbent 54 made of a hollow fiber-shaped or solid yarn-shaped fiber used in the blood cell removal module of the present embodiment will be specifically described. The blood cell removal adsorbent 54 is made of a hydrophobic polymer resin. Thereby, since the surface of the blood cell removal adsorbent 54 becomes hydrophobic, not only granulocytes, which are inflammatory cells, but also platelets can be efficiently removed by hydrophobic interaction. In addition, while suppressing side effects, inflammation symptoms derived from autoimmune diseases can be suppressed.

As the hydrophobic polymer resin, the same resin as in the above-described first embodiment can be used. Therefore, the description thereof is omitted here.

By setting Ra on the surface of the blood cell removal adsorbent to 5 to 100 nm, the adsorbability of leukocytes and platelets can be further improved. In addition, as described above, it is difficult in manufacturing to make Ra of the surface of the blood cell removal adsorbent smaller than 5. On the other hand, when Ra on the surface of the blood cell removal adsorbent is larger than 100 nm, the contribution to the adsorption of platelets (size 2 to 4 µm) decreases. Ra on the surface of the adsorbent for blood cell removal can be measured by AFM (atomic force microscope). The measurement of Ra on the surface of the adsorbent for removing blood cells in the present embodiment is performed by using SDF 400 manufactured by Seiko Instruments Co., Ltd. as a AFM, and using DFM SZDF20AL (manufactured by Seiko Instruments Co., Ltd.) as a probe. Is 10 μm × 10 μm.

The blood cell removal adsorbent made of the fiber in the present embodiment is produced by the coagulation method comprising the method for producing a hollow fiber-shaped blood cell removal adsorbent or a method for producing a solid thread blood cell removal adsorbent.

Moreover, the outer diameter of the blood cell removal adsorbent which consists of fibers in this embodiment is 0.1 mm-5 mm hollow fiber or solid yarn, and the average pore of the surface of the blood cell removal adsorbent which consists of fibers in this embodiment Iii) The diameter is 50 nm to 300 nm.

Since the adsorbent for blood cell removal made of the fibers in the present embodiment has a straight yarn shape, the patient is compared with the use of an ultrafine fiber nonwoven fabric (for example, "Sel Soba" manufactured by Asahi Kasei Clare Medical Co., Ltd.). The high viscosity of the blood can be used even when the risk of coagulation is high in the case of the blood cell removal module.

The mesh cloth in this embodiment is 20 micrometers-100 micrometers of fiber diameters (line diameter), for example, 3-80 meshes (3-80 mesh) of meshes per inch are preferable, The material of the mesh is selected from polyester, nylon, polyethylene and polypropylene.

Unlike the LCAP (lymphocyte removal therapy), the blood cell removal module according to the present embodiment does not remove lymphocytes, and therefore, there is a low risk of removing and discarding memory cells involved in immunity. In addition, the cylindrical blood cell removal adsorbent used in the blood cell removal module according to the present embodiment is, as described later, an "ada column" of the adsorbent made of cellulose acetate beads used for GCAP (granulocyte removal therapy). More platelets can be removed as compared with (manufactured by JIMRO). As a result, the inflammatory symptom of a patient can be suppressed efficiently. In addition, the blood cell removal module according to the present embodiment can be treated simply by passing all the blood, so that it is simple and high in safety, and requires an expensive device such as a centrifuge used in the conventional centrifugal separation technique. Do not

Example

Example 1:

Polyarylate resin (hereinafter PAR, number average molecular weight 25,000) was dissolved in NMP to adjust the polymer solution. The mass mixing ratio of PAR and NMP was set to 15.0: 85.0. A mixture of 60% NMP and water was used as a coagulation solution. This polymer solution was dripped at the height of about 10 cm from the liquid level of the coagulation liquid tank with the nozzle of 0.25 mm internal diameter. After sufficiently coagulating in the coagulation solution, the resultant was washed with distilled water to obtain beads for blood cell removal having a diameter of about 1.5 mm. The blood cell removal beads of Example 1 were approximately spherical, and the ratio (yield) of the shape which can be used as an adsorbent was 99.6% (calculated at 1000 beads).

As shown in Fig. 2, the obtained blood cell removing beads 190 are loaded into a cylindrical polycarbonate casing 210, and then the blood cell removing beads are made of a pair of polyester meshes 220 made of polyester. With 190 not leaking out, a header 230 having an inlet and outlet port for blood was installed and modularized. As the mesh 220, a hole having a hole smaller than the diameter of the blood cell removing beads 190 was used.

AFM measurement (10 micrometers x 10 micrometers, SPA400 by Seiko Instruments Inc., a probe: DFM SZDF20AL (made by Seiko Instruments Corporation)) confirmed that Ra of the blood cell removal beads surface of Example 1 is 15 nm.

Example 2:

The polymer solution was adjusted by dissolving in polyether sulfone resin (hereinafter PES, grade 4800P, number average molecular weight 21,000) and N-methyl-2-pyrrolidone (hereinafter NMP). The mass mixing ratio of PES and NMP was set to 15.0: 85.0. What mixed 36% of NMP in water was used as the coagulation liquid. This polymer solution was dripped at the height of about 10 cm from the liquid level of the coagulation liquid tank with the nozzle of 0.25 mm internal diameter. After sufficiently coagulating in the coagulation solution, the resultant was washed with distilled water to obtain beads for blood cell removal having a diameter of about 1.5 mm. The blood cell removal beads of Example 2 were substantially round, and the ratio of the shape usable as the adsorbent was 99.8% (calculated at 1000 beads). AFM measurement (10 micrometers x 10 micrometers, SPA400 by Seiko Instruments Inc., a probe: DFM SZDF20AL (made by Seiko Instruments Corporation)) confirmed that Ra of the blood cell removal beads surface of Example 2 is 21 nm.

Example 3:

PES (grade 4800P, number average molecular weight 21,000) and PAR (number average molecular weight 25,000) were dissolved in N-methyl-2-pyrrolidone (hereinafter NMP) to adjust the polymer solution. The mass mixing ratio of PES, PAR, and NMP was set to 10.0: 5.0: 85.0. What mixed 36% of NMP in water was used as the coagulation liquid. This polymer solution was dripped at the height of about 10 cm from the liquid level of the coagulation liquid tank with the nozzle of 0.25 mm internal diameter. After sufficiently coagulating in the coagulation solution, the resultant was washed with distilled water to obtain beads for blood cell removal having a diameter of about 1.5 mm. The blood cell removal beads of Example 3 were approximately round, and the ratio of the shape usable as the adsorbent was 99.1% (calculated at 1000 beads). By AFM measurement (10 micrometers x 10 micrometers, SPA400 by Seiko Instruments, probe: DFM SZDF20AL (made by Seiko Instruments)), it was confirmed that Ra of the blood cell removal beads surface of Example 3 is 34 nm. 3, the AFM image (10 micrometers x 10 micrometers) of the blood cell removal beads of Example 3 is shown.

Comparative Example 1:

The polymer solution was adjusted similarly to Example 3. What mixed NMP 70% in water was used as the coagulation liquid. This polymer solution was dripped at the height of about 10 cm from the liquid level of the coagulation liquid tank with the nozzle of 0.25 mm internal diameter. After solidifying sufficiently in a coagulation liquid, it wash | cleaned with distilled water and obtained the blood cell removal beads of about 1.5 mm in diameter. The blood cell removal beads of Comparative Example 1 were substantially round, and the ratio of the shape usable as the adsorbent was 72.3% (calculated at 1000 beads). AFM measurement (10 micrometers x 10 micrometers, SPA400 by Seiko Instruments Inc., a probe: DFM SZDF20AL (made by Seiko Instruments Corporation)) confirmed that Ra of the blood cell removal beads surface of the comparative example 1 is 104 nm.

Comparative Example 2:

As a blood cell removal beads of Comparative Example 2, an alumina ball (Azone; manufactured by As One Corporation) having a diameter of 2 mm was used. The AFM measurement (10 micrometers x 10 micrometers, SPA400 by Seiko Instruments, Inc., a probe: DFM SZDF20AL (made by Seiko Instruments, Inc.)) confirmed that Ra of the blood cell removal beads surface of the comparative example 2 is 124 nm.

Comparative Example 3:

As a blood cell removal beads of Comparative Example 3, cellulose acetate beads having a diameter of 2 mm (drawn from Ada column manufactured by J IMRO) were used. The AFM measurement (10 micrometers x 10 micrometers, SPA400 by Seiko Instruments Inc., a probe: DFM SZDF20AL (made by Seiko Instruments)) confirmed that Ra of the blood cell removal beads surface of the comparative example 3 is 133 nm. 4, the AFM image (10 micrometers x 10 micrometers) of the blood cell removal beads of the comparative example 3 is shown. As can be seen in FIG. 4, large irregularities exist on the surface of the blood cell removal beads of Comparative Example 3.

[White blood cell platelet adsorption test]

The blood cell removal beads (38 mL) of Examples 1 to 3 and Comparative Examples 1 to 3 were each filled in a column having a diameter of 27 mm and a length of 70 mm (capacity 40 mL). 250 mL of blood was collected from a healthy box into a blood bag, and after heparinization, the cells were circulated at 7 mL / min for 30 minutes. The number of granulocytes (neutrophils), platelet count, and lymphocyte count From the change of, the adsorption rate for each blood cell removal beads was calculated. The results are shown in Table 1. Examples 2 and 3 and Comparative Examples 1 to 3 were also modularized in the same manner as in Example 1.

     Adsorbent Ra
(nm) yield Granulocyte
absorption(%) Lymphocyte
absorption(%) Platelets
absorption(%) Solidification state during and after circulation Example 1 Polyarylate beads 15 99.6 62 5 59 Coagulation, no residual blood Example 2 Polyether
Sulfon beads 21 99.8 55 2 48 Coagulation, no residual blood Example 3 Polyarylate
Polyether
Sulfon beads
34
99.1
57
4
57
Coagulation, no residual blood Comparative Example 1 Polyarylate
Polyether
Sulfon beads
104
72.3
65
6
62
Coagulation, no residual blood Comparative Example 2 Alumina Ball 124 - 62 10 61 Solidification during circulation Comparative Example 3 Cellulose
Acetate beads 133 - 57 0 19 Coagulation, no residual blood

In the blood cell removal beads of Comparative Example 1 (RA = 104 nm), the yield which becomes a shape that can be used as an adsorbent is greatly reduced, resulting in an increase in manufacturing cost. In the blood cell removal beads of Comparative Example 2 (RA = 124 nm), the adsorption of leukocytes and platelets was confirmed, but a problem occurred that blood coagulated during column circulation. It was confirmed that the adsorption amount of platelets was low in the blood cell removal beads of Comparative Example 3 (RA = 133 nm).

In the blood cell removal beads of Examples 1 to 3, it was confirmed that blood coagulation did not occur or blood residues occurred after the circulation in the column circulation, and thus leukocytes and platelets could be adsorbed efficiently.

Example 4:

Polymer solution was adjusted using PAR, PES and NMP. The weight mixing ratio of PAR and PES was 1: 1. NMP aqueous solution was used as a coagulation liquid and a core liquid. The polymer solution was discharged into the coagulating solution together with the core liquid using a double tube spinneret to produce hollow fibers for blood cell removal, and 10,000 hollow fibers for blood cell removal were bundled to obtain a hollow fiber bundle. Moreover, as shown in FIG. 5, this hollow fiber bundle 200 is loaded in the cylindrical polycarbonate casing 210, and the hollow fiber bundle is pressed with a pair of polyester meshes 220 made of polyester. In the state, the header 230 having the port of the blood introduction outlet was installed and modularized. As the mesh 220, one having a hole smaller than the diameter of the hollow yarn was used. By AFM measurement (10 micrometers x 10 micrometers, SPA400 by Seiko Instruments Inc., a probe: DFM SZDF20AL (made by Seiko Instruments Corporation)), it was confirmed that Ra of the blood fiber removal hollow fiber surface of Example 4 is 5.2 nm.

Comparative Example 4:

As Comparative Example 4, a filler of ada column (cellulose acetate beads having a diameter of about 2 mm) that was a granulocyte adsorption column was used. By AFM measurement (10 micrometers x 10 micrometers, SPA400 by Seiko Instruments Inc., a probe: DFM SZDF20AL (made by Seiko Instruments Corporation)), it was confirmed that Ra of the bead surface of the comparative example 4 is 133 nm.

[White blood cell platelet adsorption test]

A column of 27 mm diameter and a length of 70 mm (inner capacity 40 mL) was filled with the hollow fiber for removing blood cells of Example 4 and beads of Comparative Example 4 each corresponding to 3260 cm 2. Adsorption rate for each module was obtained from the change of granulocytes (neutrophils), platelet count, and lymphocyte count when 250 mL of blood was collected from the case and circulated at 7 mL / min after heparinization for 30 minutes. Was calculated. The results are shown in Table 2.

Adsorption rate (n = 6) Granulocytes (neutrophils) Platelets Lymphocyte Example 4 67% 78% 0% Comparative Example 4 57% 19% 0%

As shown in Table 2, when the hollow fiber for blood cell removal of Example 4 was used, it was confirmed that both granulocytes and platelets are efficiently removed. On the other hand, when the beads of Comparative Example 4 were used, platelet removal was insufficient.

Example 5:

Polyarylate resin (hereinafter PAR; number average molecular weight 25,000, UNICHICASE, trade name: U polymer) and polyether sulfone resin (hereinafter PES, grade 4800P, number average molecular weight 21,000, Sumitomo Chemical Co., Ltd., product name: Sumica Excel PES) And the polymer stock solution was adjusted using N-methylpyrrolidone (NMP). The weight mix ratio of PAR, PES, and NMP was 7.5: 7.5: 85.0. N-methylpyrrolidone aqueous solution (thing mixed with NMP in water 60%) was made into the coagulation liquid and the core liquid. The above polymer stock solution is discharged into the coagulating solution together with the core fluid by using a double-pipe spinneret to form a hollow fiber membrane, and continuously cut. The hollow fiber-like short fibers having an outer diameter of 0.3 mm, an inner diameter of 0.2 mm, and a length of 5 mm are obtained. An adsorbent for removing blood cells was obtained. The means for cutting the hollow fiber membrane into short fibers is not particularly limited, but a known fiber cutting device using a cutter roll from an industrial point of view (Japanese Patent Application Laid-Open No. 5-96033, Japanese Patent Laid-Open No. 9-277190, See Japanese Patent Application Laid-Open No. Hei 6-27092).

The surface roughness of the blood cell removal adsorbent of this example was measured using AFM (10 µm x 10 µm, SPA400 manufactured by Seiko Instruments, Probe: DFM SZDF20AL (manufactured by Seiko Instruments)), and Ra = 6.2 nm. Moreover, the average pore diameter was 25.4 nm. In addition, the average pore diameter was measured using the porosimeter (PoreMaster-60) made from Yuasa Ionics.

In the leukocyte-platelet adsorption test, the adsorbent was filled into a polycarbonate case (column) having an inner diameter of 27 mm and a length of 70 mm, and filled with about 0.1 m 2 of short fibers in terms of an external surface area. The ratio of the blood cell removal adsorbent length to the inner diameter of the case is 5 mm / 27 mm x 100 = 18.5%. The filling rate of the blood cell adsorbent for the volume of the case is 48%.

250 mL of blood was collected from the tendon box, and the change in granulocyte (neutrophil) count, platelet count, and lymphocyte count when circulated at 7 mL / min for 30 minutes after heparinization was performed. The adsorption rate for the blood cell adsorbent was calculated. As a result, the adsorption rates of granulocyte count, platelet count and lymphocyte count were 54%, 61%, and 2%, respectively.

The blood cell removal adsorbent according to Example 5 exhibited sufficient adsorption capacity to granulocytes and platelets as inflammatory cells, and the adsorption capacity of lymphocytes to be left in the body as memory cells was low. In addition, the air at the time of priming was also easy, blood coagulation was not seen.

Example 6:

A hollow fiber membrane was produced in the same manner as in Example 5, and the obtained hollow fiber membrane was cut into a length of 10 mm (0.3 mm outside diameter and 0.2 mm inside diameter) to obtain an adsorbent for removing blood cells of hollow fiber-shaped short fibers. The ratio of the length of the blood cell removal adsorbent to the inner diameter of the case is 10 mm / 27 mm x 100 = 37.0%. The filling rate of the blood cell adsorbent for the volume of the case is 36%.

The blood cell adsorption test was carried out in the same manner as in Example 1 with respect to the blood cell removal adsorbent according to Example 6. As a result, the adsorption rates of granulocyte count, platelet count and lymphocyte count were 55%, 58%, and 3%, respectively.

The blood cell removal adsorbent according to Example 6 exhibited sufficient adsorption capacity to granulocytes and platelets as inflammatory cells, and low adsorption capacity of lymphocytes to be left in the body as memory cells. In addition, the air at the time of priming was also easy, and blood coagulation was not seen.

Example 7:

A hollow fiber membrane was produced in the same manner as in Example 5, and the obtained hollow fiber membrane was cut to 15 mm in length (0.3 mm in outer diameter and 0.2 mm in inner diameter) to obtain an adsorbent for removing blood cells of hollow fiber-shaped short fibers. The ratio of the length of the blood cell removal adsorbent to the inner diameter of the case is 15 mm / 27 mm x 100 = 55.6%. The filling rate of the blood cell removal adsorbent relative to the volume of the case is 21%.

The blood cell adsorption test was carried out in the same manner as in Example 1 with respect to the blood cell removal adsorbent according to Example 7. As a result, the adsorption rates of granulocyte count, platelet count and lymphocyte count were 51%, 55%, and 3%, respectively.

The blood cell removal adsorbent according to Example 7 exhibited sufficient adsorption capacity to granulocytes and platelets as inflammatory cells, and the adsorption capacity of lymphocytes to be left in the body as memory cells was low. In addition, the air at the time of priming was also easy, and blood coagulation was not seen.

Comparative Example 5:

A hollow fiber membrane was produced in the same manner as in Example 5, and the obtained hollow fiber membrane was cut to a length of 20 mm (0.3 mm outside diameter and 0.2 mm inside diameter) to obtain an adsorbent for removing blood cells of hollow fiber-shaped short fibers. The ratio of the length of the blood cell removal adsorbent to the inner diameter of the case is 20 mm / 27 mm x 100 = 74.1%. The filling rate of the blood cell adsorbent for the volume of the case is 15%.

The blood cell adsorption test was carried out in the same manner as in Example 5 with respect to the blood cell removal adsorbent according to Comparative Example 5. As a result, the adsorption rates of granulocyte count, platelet count and lymphocyte count were 53%, 57%, and 2%, respectively.

The blood cell removal adsorbent according to Comparative Example 5 exhibited sufficient adsorption capacity to granulocytes and platelets as inflammatory cells, and the adsorption capacity of lymphocytes to be left in the body as memory cells was low. However, since the movement of the fibers in the case is limited, the fibers are trapped or the air is difficult to escape during priming, and after the circulation is finished, blood coagulation is observed in the adsorbent for removing blood cells.

Example 8:

The polymer stock solution was adjusted using PAR (number average molecular weight 25,000, UNICHICASE, brand name: U polymer) and NMP. The weight mixing ratio of PAR and NMP was 15:85. N-methylpyrrolidone aqueous solution (thing which mixed NMP with water 60%) was made into the coagulation liquid. The polymer stock solution was discharged into a coagulation solution using a spinneret to prepare a solid yarn film, and then cut continuously to obtain an adsorbent for removing blood cells of a solid yarn-like short fiber having an outer diameter of 0.25 mm and a length of 5 mm. The ratio of the length of the blood cell removal adsorbent to the inner diameter of the case is 5 mm / 27 mm x 100 = 18.5%. The filling rate of the blood cell adsorbent for the volume of the case is 42%.

The surface roughness of the blood cell removal adsorbent of this example was measured using AFM (10 μm × 10 μm, SPA400 manufactured by Seiko Instruments, Probe: DFM SZDF20AL (manufactured by Seiko Instruments)), and Ra = 3.4 nm. In addition, the average pore diameter was 16.7 nm. In addition, the average pore diameter was measured using the porosimeter (PoreMaster-60) made from Yuasa Ionics.

The blood cell adsorption test was carried out in the same manner as in Example 5 with respect to the blood cell removal adsorbent according to Example 8. As a result, the adsorption rates of granulocyte count, platelet count and lymphocyte count were 65%, 62%, and 6%, respectively.

The blood cell removal adsorbent according to Example 8 exhibited sufficient adsorption capacity to granulocytes and platelets as inflammatory cells, and the adsorption capacity of lymphocytes to be left in the body as memory cells was low. In addition, the air during the priming is easy to bleed, blood coagulation was not seen.

Example 9:

A solid yarn film was produced in the same manner as in Example 8, and the resulting solid yarn film was cut to a length of 10 mm (outer diameter of 0.25 mm) to obtain an adsorbent for removing blood cells of solid yarn-like short fibers. The ratio of the length of the blood cell removal adsorbent to the inner diameter of the case is 10 mm / 27 mm x 100 = 37.0%. The filling rate of the blood cell adsorbent for the volume of the case is 31%.

The blood cell adsorption test was carried out in the same manner as in Example 5 with respect to the blood cell removal adsorbent according to Example 9. As a result, the adsorption rates of granulocyte count, platelet count and lymphocyte count were 66%, 60%, and 7%, respectively.

The blood cell removal adsorbent according to Example 9 exhibited sufficient adsorption capacity to granulocytes and platelets as inflammatory cells, and the adsorption capacity of lymphocytes to be left in the body as memory cells was low. In addition, the air during the priming is easy to bleed, blood coagulation was not seen.

Example 10

A solid yarn film was produced in the same manner as in Example 8, and the obtained solid yarn film was cut to 15 mm in length (0.25 mm in outer diameter) to obtain an adsorbent for removing blood cells of solid yarn-like short fibers. The ratio of the length of the blood cell removal adsorbent to the inner diameter of the case is 15 mm / 27 mm x 100 = 55.6%. The filling rate of the adsorbent for removing blood cells with respect to the volume of the case is 20%.

The blood cell adsorption test was performed in the same manner as in Example 5 with respect to the blood cell removal adsorbent according to Example 10. As a result, the adsorption rates of granulocyte count, platelet count and lymphocyte count were 64%, 58%, and 5%, respectively.

The blood cell removal adsorbent according to Example 10 exhibited sufficient adsorption capacity to granulocytes and platelets as inflammatory cells, and the adsorption capacity of lymphocytes to be left in the body as memory cells was low.

In addition, the air during the priming is easy to bleed, blood coagulation was not seen.

Example 11:

The polymer stock solution was adjusted using PES (grade 4800P, number average molecular weight 21,000, Sumitomo Chemical Co., Ltd., brand name: Sumica Excel PES), and NMP. The weight mixing ratio of PES and NMP was 15:85. N-methylpyrrolidone aqueous solution (thing which mixed NMP with water 60%) was made into the coagulation liquid. The polymer stock solution described above was discharged into a coagulation solution using a spinneret to prepare a solid yarn film, which was continuously cut to obtain an adsorbent for removing blood cells of solid yarn-shaped short fibers having an outer diameter of 0.25 mm and a length of 10 mm. The ratio of the length of the blood cell removal adsorbent to the inner diameter of the case is 10 mm / 27 mm × 100 = 37%. The filling rate of the adsorbent for removing blood cells with respect to the volume of the case is 28%.

The surface roughness of the blood cell removal adsorbent of this example was measured using AFM (10 μm × 10 μm, SPA400 manufactured by Seiko Instruments, Probe: DFM SZDF20AL (manufactured by Seiko Instruments)), and Ra was 5.2 nm. In addition, the average pore diameter was 12.4 nm. In addition, the average pore diameter was measured using the porosimeter (PoreMaster-60) made from Yuasa Ionics.

The blood cell adsorption test was carried out in the same manner as in Example 1 with respect to the blood cell removal adsorbent according to Example 11. As a result, the adsorption rates of granulocyte count, platelet count and lymphocyte count were 53%, 48%, and 0%, respectively.

The blood cell removal adsorbent according to Example 11 exhibited sufficient adsorption capacity to granulocytes and platelets as inflammatory cells, and the adsorption capacity of lymphocytes to be left in the body as memory cells was low. In addition, the air during the priming is easy to bleed, blood coagulation was not seen.

Example 12:

The hollow fiber membrane was taken out from the Nipro Corporation diaphragm FB-150F using the cellulose acetate hollow fiber membrane (inner diameter 200 micrometers, outer diameter 230 micrometers), it cut | disconnected to 10 mm length, and the blood cell removal of a hollow fiber-shaped short fiber An adsorbent was obtained. The filling rate of the blood cell adsorbent for the volume of the case is 31%.

The blood cell adsorption test was carried out in the same manner as in Example 1 with respect to the blood cell removal adsorbent according to Example 12. As a result, the adsorption rates of granulocyte count, platelet count and lymphocyte count were 55%, 15% and 1%, respectively.

The blood cell removal adsorbent according to Example 12 exhibited the ability to adsorb granule cells as inflammatory cells. On the other hand, the platelet and lymphocyte adsorption capacity was low. In addition, the air during the priming is easy to bleed, blood coagulation was not seen.

Table 3 shows all the information about the blood cell removal adsorbent and the blood cell adsorption test for Examples 5 to 12 and Comparative Example 5.

For removing blood cells
Adsorbent fiber
Length
(mm) case
% Of inner diameter Granulocyte
absorption(%) Lymphocyte
absorption(%) Platelets
absorption(%) Bleeding
Coagulation For removing blood cells
Filling rate of adsorbent (%) Example
5 Polyarylate
Polyethersulfone Heavy Industries
5
18.5
54
2
61 Good deflation
No blood clotting
48 Example
6 Polyarylate
Polyethersulfone Heavy Industries
10
37.0
55
3
58 Good deflation
No blood clotting
36 Example
7 Polyarylate
Polyethersulfone Heavy Industries
15
55.6
51
3
55 Good deflation
No blood clotting
21 Comparative Example
5 Polyarylate
Polyethersulfone Heavy Industries
20
74.1
53
2
57 Good deflation
Blood clotting
15 Example
8 Polyarylate solid yarn 5 18.5 65 6 62 Good deflation
No blood clotting 42 Example
9 Polyarylate solid yarn 10 37.0 66 7 60 Good deflation
No blood clotting 31 Example
10 Polyarylate solid yarn 15 55.6 64 5 58 Good deflation
No blood clotting 20 Example
11 Polyethersulfone solid yarn 10 37.0 53 0 48 Good deflation
No blood clotting 28 Example
12 Cellulose
Triacetate hollow fiber
10
37.0
55
One
15 Good deflation
No blood clotting
31

Example 13:

Polyarylate resin (hereinafter PAR, number average molecular weight 25,000, UNICHICASE, trade name: U polymer) and polyether sulfone resin (hereinafter PES, grade 4800P, number average molecular weight 21,000, Sumitomo Chemical Co., Ltd., product name: Sumica Excel PES) And the polymer stock solution was adjusted using N-methylpyrrolidone (NMP). The weight mix ratio of PAR, PES, and NMP was 7.5: 7.5: 85.0. N-methylpyrrolidone aqueous solution (thing mixed with NMP in water 60%) was made into the coagulation liquid and the core liquid. The polymer stock solution described above was discharged into the coagulation solution together with the core fluid using a double-pipe spinneret to produce a hollow fiber membrane, and subsequently cut, and the hollow fiber-like short fibers having an outer diameter of 300 µm, an inner diameter of 200 µm and a length of 70 mm An adsorbent for removing blood cells was obtained.

The surface roughness of the blood cell removal adsorbent of this example was measured using AFM (10 μm × 10 μm, SPA400 manufactured by Seiko Instruments, Probe: DFM SZDF20AL (manufactured by Seiko Instruments)), and Ra was 5.2 nm. In addition, the average pore diameter was 25.4 nm.

The hollow fiber-shaped adsorbent for removing blood cells (outer diameter 300 µm, length 70 mm) of this embodiment is arranged side by side in a plane shape with about 3,500 pieces thereon, and a mesh made of polyester resin which is a mesh cloth (70 mesh, line) In a state where the diameter: 71 µm) was overlapped, a heat sealer was used, and both ends of the blood cell removal adsorbent and the mesh were fused to seal the end surface of the blood cell removal adsorbent (adsorption surface area was about 2,300 cm 2). Next, each outer end portion is cut out from the fused portion and wound along the arrangement direction of the blood cell removal adsorbent, and the cylindrical blood cell removal consists of a bundle of blood cell removal adsorbents interposed through a mesh serving as a spacer. An adsorbent was obtained.

As shown in FIG. 8, the obtained cylindrical blood cell removal adsorbent 350 was loaded into a polycarbonate case 20 (full length: 70 mm, inner diameter: 27 mm, capacity: 40 mL) to introduce blood. A pair of headers 40a and 40b having a sphere and a blood outlet were mounted to prepare a module A for removing blood cells.

Comparative Example 6:

A filler of Ada column (manufactured by JIMRO), which is a granulocyte adsorption column (cellulose acetate beads having a diameter of about 2 mm, Ra = 133 nm), was made of the same polycarbonate case as in Example 1 (total length: 70 mm, inner diameter: 27 mm). , Volume: 40 mL), and a pair of headers having a blood inlet and a blood outlet are mounted to prepare a module B for blood cell removal.

[Assessment Methods]

After 500 mL of blood was collected from the case, heparinized, divided into 250 mL into a blood pack, and each blood was refluxed at 7 mL / min for 30 minutes, followed by granulocyte (neutrophil) count, platelet count, and lymphocyte count. From the change, the adsorption rate of each blood cell removal module was calculated. The results are shown in Table 4 below. In addition, this is the average value of the result measured 6 times.

Adsorption rate (%) Granulocytes (neutrophils) Platelets Lymphocyte Example 13 67 78 0 Comparative Example 6 57 19 0

From Table 4, it can be seen that the blood cell removal module A of Example 13 has a much higher platelet adsorption rate than the blood cell removal module B of Comparative Example 6.

Example 14

About 8,000 hollow fiber-shaped adsorbents for removing blood cells (outer diameter 300 µm, length 12 mm) obtained in Example 13 were arranged side by side in a planar shape, on which a mesh made of polyester resin, which was a mesh cloth (70 mesh) , Line diameter: 100 μm), a heat sealer was used, and both ends of the blood cell removal adsorbent were fused to the mesh to seal the end surface of the blood cell removal adsorbent (adsorption surface area was about 0.9 m 2). . Next, each outer end portion is cut out from the fused portion and wound along the arrangement direction of the blood cell removal adsorbent, and the cylindrical blood cell removal consists of a bundle of blood cell removal adsorbents interposed through a mesh serving as a spacer. An adsorbent was obtained.

As shown in FIG. 8, the obtained cylindrical blood cell removal adsorbent 350 was loaded into a polycarbonate case 20 (full length: 185 mm, inner diameter: 59 mm, capacity: 324 mL) to introduce blood. A pair of headers 40a, 40b having a sphere and a blood outlet were mounted to prepare a blood cell removal module C.

Reference Example:

Polyarylate resin (hereinafter PAR, number average molecular weight 25,000, UNICHICASE, trade name: U polymer) and polyether sulfone resin (hereinafter PES, grade 4800P, number average molecular weight 21,000, Sumitomo Chemical Co., Ltd., product name: Sumica Excel PES) And the polymer stock solution was adjusted using N-methylpyrrolidone (NMP). The weight mixing ratio of PAR, PES, and NMP was set to 7.5: 7.5: 85.0. N-methylpyrrolidone aqueous solution (thing which mixed NMP with water 60%) was made into the coagulation liquid. This polymer solution was dripped at the height of about 20 cm from the liquid level of the coagulation liquid tank with the nozzle of 0.25 mm internal diameter. After solidifying sufficiently in the coagulation liquid, the resultant was washed with distilled water to obtain beads for blood cell removal having a diameter of about 1 mm.

About 300,000 granules (about 290 mL) (adsorption surface area is about 0.9 m 2) of the blood cell removing beads obtained in the reference example were loaded into a polycarbonate case (full length: 185 mm, inner diameter: 59 mm, capacity: 324 mL). Then, a pair of headers having a blood inlet port and a blood outlet port was attached to produce a blood cell removal module D.

[Assessment Methods]

3 L of heparinized bovine blood (hematocrit blood: 32%) was passed through the circulation in a blood cell removal module at 50 mL / min, and the inlet pressure of the blood inlet of the blood cell removal module after 20 minutes The outlet pressure was measured to calculate the pressure drop in the module. The results are shown in Table 5 below.

Module Inlet Pressure (Pa) Module outlet pressure (Pa) Pressure loss (Pa) Reference Example 6,000 3,866 2,133 Example 14 4,666 4,000 666

From Table 5, it can be seen that the blood cell removal module C of Example 14 has a smaller pressure loss than the blood cell removal module D for filling beads of the reference example. In addition, the adsorption rate of granulocytes (neutrophils) and platelets was the same as that for the blood cell removal module C of Example 14, and the blood cell removal module D of the beads filling of the reference example.

[bookkeeping]

Another preferable aspect of this invention is as follows.

The blood cell removal module according to any aspect of the present invention includes a case provided with an inlet portion through which blood flow is introduced before blood cell removal and an outlet portion through which blood flow after blood cell removal is discharged, an adsorbent for short-fiber blood cell removal accommodated in the case, and an inlet. And a mesh for retaining the blood cell removal adsorbent in the case, and a short-fiber blood cell removal adsorbent housed in the case, wherein the length of the blood cell removal adsorbent is the inner diameter of the case. It is characterized by 1 to 60%.

According to this aspect, white blood cells and platelets can be efficiently removed while suppressing problems such as bleeding before use and in-circulation coagulation during blood circulation. Moreover, it is more preferable that the length of the blood cell removal adsorbent is 18 to 56% of the case inner diameter. According to this, the said effect can be heightened further.

In the above aspect, the filling rate of the adsorbent for removing blood cells to the volume of the case may be 20 to 60%.

In the above aspect, the blood cell removal adsorbent may be a hollow fiber or a solid yarn fiber. Moreover, when the adsorbent for blood cell removal is made into a hollow fiber shape, the amount of material used can be reduced as compared with solid yarns. In addition, blood cell adsorption on the inner surface side can also be expected.

In the above aspect, the blood cell removal adsorbent may be made of a hydrophobic polymer resin. In this case, the hydrophobic polymer resin may be a polyarylate resin having a repeating unit represented by the following general formula (1).

In addition, the hydrophobic polymer resin may include a polyether sulfone resin having a repeating unit represented by the following formula (2) or formula (3).

In general formula (2), R <3> and R <4> is a C1-C5 lower alkyl group, and R <3> and R <4> may be same or different, respectively.

In the above aspect, the hydrophobic polymer resin may include a polyarylate resin having a repeating unit represented by the general formula (1) and a polyether sulfone resin having a repeating unit represented by the general formula (2) or the general formula (3). .

The blood cell removal module of the above aspect may be used to remove white blood cells and platelets in blood.

In addition, the appropriate combination of the above-described elements can also be included in the scope of the invention seeking protection by a patent by the present patent application.

Moreover, as another preferable aspect, it is as follows.

(I) Both ends of the blood cell removal adsorbent comprising a casing provided with an inlet portion through which blood flow flows before blood cell removal and an outlet portion through which blood flow is discharged after blood cell removal, and a plurality of arranged hollow fiber-shaped or solid yarn fibers A blood cell removal module having a tubular blood cell removal adsorbent formed by winding an integrated mesh cell-like cloth fixed in a network-like cloth capable of passing blood along the arrangement direction of the blood cell removal adsorbent.

(II) Furthermore, it is a blood cell removal module as described in said (I) provided in the said inlet part and the said exit part, respectively, and provided with the mesh which hold | maintains the said blood cell removal adsorbent in the said case.

(III) The adsorbent for removing blood cells is at least a polyarylate resin having a repeating unit represented by the following formula (1) and a polyether sulfone resin having a repeating unit represented by the formula (2) or formula (3). It is a blood cell removal module as described in said (I) or (II) containing a kind of hydrophobic polymer resin.

In general formula (1), R1 and R2 are C1-C5 lower alkyl groups, and R1 and R2 may be same or different, respectively.

In general formula (2), R <3> and R <4> is a C1-C5 lower alkyl group, and R <3> and R <4> may be same or different, respectively.

(IV) The blood cell removal module according to any one of (I) to (III), which is used for removal of leukocytes and platelets in blood.

(V) a step of fixing both ends of the blood cell removal adsorbent consisting of a plurality of hollow fiber-like or solid-fiber fibers arranged to form a blood cell removal adsorbent-integrated mesh cloth, The blood cell removal adsorbent-integrated mesh cloth is rolled along the arrangement direction of the blood cell removal adsorbent to form a cylindrical blood cell removal adsorbent, and the blood flow before the blood cell removal is It is a manufacturing method of a blood cell removal module having a process for accommodating the inlet portion and the outlet portion for the discharge of blood flow after blood cell removal is installed.

(VI) In the step of forming a blood-removing adsorbent-integrated mesh cloth, the blood-removing adsorbent is hollow fiber, and both ends of the blood cell-removing adsorbent are fixed to the mesh-like cloth through which the blood can pass through by heat fusion. The hollows at both ends of the heat-sealed blood cell removal adsorbent are a manufacturing method of the blood cell removal module according to the above (V).

According to the above aspect, the pressure loss at the time of blood cell removal can be reduced compared with the beads-like blood cell removal adsorbent.

Further, the mesh transition functions as a spacer of the blood cell removal adsorbent composed of a plurality of hollow fiber or solid yarn fibers, and the distance between fibers of the blood cell removal adsorbent housed is substantially uniform in the blood cell removal module. In addition, appropriate voids can be formed. Thus, blockage of blood flow in the blood cell removal module is suppressed. As a result, the blood cell adsorption efficiency is improved, and since the mesh fixing the end of the blood cell removal adsorbent made of fibers as described above is not forcibly used, the number of parts can be reduced, and the manufacturing process is simplified.

In addition, when the blood cell removing adsorbent is hollow fiber, the hollows at both ends of the heat-sealed blood cell removing adsorbent are sealed, so that blood flows into the hollow fiber of the blood cell removing adsorbent to cause residual blood at the time of blood cell removal. Can be suppressed.

In addition, although this invention was demonstrated in detail, the scope of the present invention is not limited to what was described above.

Also, Japanese Patent Application No. 2008-109381, filed April 18, 2008, and Japanese Patent Application No. 2008-154418, filed June 12, 2008, and Japanese Patent Application No. 2008-299521, filed November 25, 2008, and 2009 The description of the specification, the claims, the drawings, and the summary of the specification disclosed in Japanese Patent Application No. 2009-098289, filed April 14, are incorporated herein.

The present invention is suitable for blood cell removal.

1, 10, 300: blood cell removal module 20: case
21 case body 22, 24 blood inlet outlet
30a, 30b: mesh 40a, 40b: header
350, 350a: Adsorbent for removing cylindrical blood cells
52: mesh cloth 54: adsorbent for removing blood cells
56: fusion
60: one-piece mesh cloth fabric for adsorption of blood cells
70: welding device
100: blood cell beads removal apparatus
110: liquid tank 120: pump
130 nozzle 140 coagulation bath
144: coagulation liquid recovery tank 150: beads for removing blood cells

Claims (7)

In the blood cell removal adsorbent used for the removal of white blood cells and platelets in the blood,
It is formed of hydrophobic polymer resin, the surface center line average roughness (Ra) is 5-100 nm,
The said hydrophobic polymer resin is a polyarylate resin which has a repeating unit represented by following General formula (1), The number average molecular weight of the said polyarylate resin is 20000-30000, The adsorbent for blood cell removal characterized by the above-mentioned.

In general formula (1), R1 and R2 are C1-C5 lower alkyl groups, and R1 and R2 may be same or different, respectively. The method of claim 1,
The said hydrophobic polymer resin contains the polyether sulfone resin which has a repeating unit represented by following General formula (2) or General formula (3), The blood cell removal adsorption body characterized by the above-mentioned.

In general formula (2), R <3> and R <4> is a C1-C5 lower alkyl group, and R <3> and R <4> may be same or different, respectively.

3. The method according to claim 1 or 2,
The blood cell removal adsorbent whose number average molecular weight of the said polyether sulfone resin is 15000-30000. The method of claim 1,
A blood cell removal adsorbent having a centerline average roughness (Ra) of the surface of 5 to 34 nm. The method of claim 1,
An adsorbent for removing blood cells, which has a bead shape. The method of claim 1,
An adsorbent for removing blood cells, which is a hollow fiber or solid yarn fiber. delete

Images